1. Field of the Invention
This invention relates generally to the fields of molecular biology and molecular medicine and more specifically to proteins involved in the regulation of immunological responses and cell growth
2. Background Information
Immunological responses can be broadly classified as humoral and cell-mediated. Humoral responses are mediated by antibody molecules present in plasma, lymph or tissue fluids and produced by plasma cells that differentiate from immature B cells. An antibody has both recognition and effector function that plays a key role in eliminating bacteria, neutralizing viruses and in triggering degranulation of mast cells and basophils. Cell-mediated immune responses are those mediated by antigen-specific T cells and various nonspecific cells of the immune system, such as natural killer cells, phagocytic cells and other white blood cells. Cell-mediated responses protect against infections due to intracellular bacteria, viruses or yeasts.
Despite the separate classifications of immunological responses, the humoral immune response is highly dependent for its function on a class of T cells known as T helper cells (T.sub.H cells). Antigens that require T.sub.H cells to elicit a humoral immune response are known as T-dependent antigens. During the humoral response to T-dependent antigens, T.sub.H cells make direct contact with B cells, which results in B cell proliferation and immunoglobulin (Ig) class switching from the IgM class to IgG, IgA or IgE antibody classes. Various receptor-ligand interactions are involved in mediating contact between a T.sub.H cell and a B cell during the response to a T-dependent antigen. In particular, CD40-CD40 ligand (CD40L) pairing is critical to achieving this cell-cell interaction.
CD40L and CD40 are both transmembrane glycoproteins that are homologous to tumor necrosis factor (TNF) and TNF receptors, (TNF-R), respectively. CD40 has a role in a variety of B cell functions, such as inducing Ig class-switching, acting as a cofactor with specific antigen and certain lymphokines for B cell mitogenesis, providing signals that prevent apoptotic cell death and triggering B cell adhesion to other cells. CD40L is not expressed on resting T.sub.H cells but can be induced after the cell contacts specific antigen.
The function of CD40/CD40L interactions in the immune response is revealed by hereditary abnormalities of CD40L, which cause an X-linked immunodeficiency syndrome. This syndrome is characterized by hyper-production of IgM, reduced levels of IgG, failure to produce IgA and IgE and absence of germinal centers in lymphoid tissues. The germinal centers are structures associated with T-dependent antibody responses. Nearly identical abnormalities are seen in transgenic mice that do not express CD40. These results indicate that the CD40/CD40L interaction provides a non-redundant pathway required for achieving T-dependent antibody responses in vivo.
It currently is unclear how CD40 transduces its CD40L-binding signal into a B cell. Since CD40 is present on the cell surface, its action likely is mediated by CD40 binding to one or more intracellular proteins, which ultimately effect signal transduction pathways that control Ig class-switching, cell proliferation and cell survival. However, the cytoplasmic domain of CD40 provides no clues as to how intracellular signalling is accomplished since the domain lacks homology to kinases or other enzymes known for mediating intracellular signalling.
The identification of intracellular proteins that can associate with CD40 and transduce the CD40L-binding signal into a cell would provide a means to manipulate various cellular functions, including, for example, humoral immune responses and apoptosis. Thus, a need exists to identify proteins that associate with CD40. The present invention satisfies this need and provides additional advantages as well.